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Sex dimorphic actions of rosiglitazone in generalised peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-deficient mice.

ABSTRACT: The aim of this study was to determine the dependency on peroxisome proliferator-activated receptor-gamma (PPAR-gamma) of insulin sensitisation and glucose homeostasis by thiazolidinediones using a global Ppar-gamma (also known as Pparg)-knockout mouse model.Global Mox2-Cre-Ppar-gamma-knockout (MORE-PGKO) mice were treated with rosiglitazone and analysed for insulin sensitivity and glucose metabolism. Metabolic and hormonal variables were determined. Adipose and other tissues were measured and analysed for gene expression.Rosiglitazone induced regrowth of fat in female but not male MORE-PGKO mice, and only in specific depots. Insulin sensitivity increased but, surprisingly, was not associated with the typical changes in adipokines, plasma NEFA or tissue triacylglycerol. However, increases in alternatively activated macrophage markers, which have been previously associated with metabolic improvement, were observed in the regrown fat. Rosiglitazone improved glucose homeostasis but not insulin sensitivity in male MORE-PGKO mice, with further increase of insulin associated with an apparent expansion of pancreatic islets.Stimulating fat growth by rosiglitazone is sufficient to improve insulin sensitivity in female mice with 95% PPAR-gamma deficiency. This increase in insulin sensitivity is not likely to be due to changes typically seen in adipokines or lipids but may involve changes in macrophage polarisation that occur independent of PPAR-gamma. In contrast, rosiglitazone improves glucose homeostasis in male mice with similar PPAR-gamma deficiency by increasing insulin production independent of changes in adiposity. Further, the insulin-sensitising effect of rosiglitazone is dependent on PPAR-gamma in this male lipodystrophic model.

SUBMITTER: Duan SZ

PROVIDER: S-EPMC2896206 | biostudies-other | 2010 Jul

REPOSITORIES: biostudies-other

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Sex dimorphic actions of rosiglitazone in generalised peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-deficient mice.

Duan S Z SZ Usher M G MG Foley E L EL Milstone D S DS Brosius F C FC Mortensen R M RM

Diabetologia 20100417 7

<h4>Aims/hypothesis</h4>The aim of this study was to determine the dependency on peroxisome proliferator-activated receptor-gamma (PPAR-gamma) of insulin sensitisation and glucose homeostasis by thiazolidinediones using a global Ppar-gamma (also known as Pparg)-knockout mouse model.<h4>Methods</h4>Global Mox2-Cre-Ppar-gamma-knockout (MORE-PGKO) mice were treated with rosiglitazone and analysed for insulin sensitivity and glucose metabolism. Metabolic and hormonal variables were determined. Adipo ...[more]

PMID: 20401461

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Project description:Apolipoprotein E (apoE) and its receptor, very low density lipoprotein receptor (VLDLR), are involved in fat accumulation in adipocytes. Here, we investigated the effect of a peroxisome proliferator-activated receptor (PPAR) gamma agonist, rosiglitazone, on regulation of VLDLR expression both in white adipose tissue (WAT) of obese mice and in cultured adipocytes. Furthermore, to determine whether rosiglitazone directly regulates transcription of the VLDLR gene, we carried out luciferase assay with a reporter gene containing mouse VLDLR promoter region, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay. Four-day treatment with rosiglitazone increased the expression of VLDLR in WAT of ob/ob mice. Moreover, rosiglitazone increased the expression of VLDLR in cultured adipocytes. The PPAR-responsive element (PPRE)-directed mutagenesis analyses revealed that the PPRE motif in the VLDLR promoter region plays a significant role in transcriptional activation of the VLDLR gene in adipocytes. In addition, electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that endogenous PPARgamma directly binds to this functional PPRE motif in the VLDLR promoter region. We also investigated the effects of rosiglitazone on insulin sensitivity and lipid accumulation in both ob/ob mice and apoE-deficient ob/ob mice. Rosiglitazone ameliorated insulin sensitivity in both ob/ob mice and apoE-deficient ob/ob mice, possibly through decreasing the expression of monocyte chemoattractant protein-1 (MCP-1), increasing the expression of superoxide dismutase 1 (SOD1) in WAT, and increasing plasma adiponectin concentration. In ob/ob mice, body weight and WAT weight were significantly higher in the mice treated with rosiglitazone than those treated with vehicle. However, in apoE-deficient ob/ob mice, no significant difference in body weight or WAT weight was observed between the vehicle-treated group and the rosiglitazone-treated group. Moreover, rosiglitazone did not increase body weight and WAT weight in VLDLR-deficient mice. These findings indicate that rosiglitazone directly increases VLDLR expression, thereby enhancing apoE-VLDLR-dependent lipid accumulation in adipocytes.

Dataset Information

Sex dimorphic actions of rosiglitazone in generalised peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-deficient mice.

Publications

Sex dimorphic actions of rosiglitazone in generalised peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-deficient mice.

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